Each year, thousands of individuals sustain spinal cord and/or brain injuries that result in motor dysfunction including partial or complete paralysis. Many of these injuries are the result of physical trauma, such as injuries sustained in vehicular accidents, violence and falls, while other injuries result from hereditary disorders such as multiple sclerosis or other medical conditions such as stroke.
Axons in the peripheral nervous system (PNS) vigorously regenerate after injury; however, severed axons in the CNS are unable to regenerate. The inability of adult CNS axons to regenerate is thought to be due to a combination of factors including: rapid death of injured neurons, intrinsically reduced capacity of adult neurons to grow when injured, lack of needed trophic molecules to support growth, and the presence of an environment that is non-permissive for growth (Woolf, Neuron 38: 153-156 (2003)). This hostile growth environment was further supported by the fact that adult CNS axons were capable of growing in a PNS-like environment (David and Aguayo Science, 214:931-933 (1981)), while PNS axons were still incapable of growing in a CNS environment (Schwab and Caroni, J Neurosci 8:2381-2393 (1988)).
One hypothesis for the difference in axonal regeneration observed in the PNS but not in the CNS is the presence of inhibitory molecules in CNS myelin sheath (Lee et al., Nature Rev Drug Discov 2:872-879 (2003)). The identification of several myelin-derived proteins which are preferentially expressed in the CNS supports this hypothesis. Nogo, OMgp, and MAG are all expressed in the CNS and have been demonstrated to inhibit neurite outgrowth (Chen et al., Nature 403:434-439 (2000); Grandpre et al., Nature 403:439-444 (2000); Prinjha et al., Nature 403:383-384 (2000); Mukhopadhyay et al., Neuron 13:805-811 (1994); Kottis et al., J Neurochem 82:1566-1569 (2002)). Each of these three inhibitors of axonal growth bind with high affinity to NogoR (Foumier et al., Nature 409:341-346 (2001); Domeniconi et al., Neuron 35:283-290 (2002); Wang et al., Nature 417:941-944 (2002)). NogoR is a glycosyl phosphatidylinositol-linked transmembrane protein and because of this, at least one other co-receptor must exist which can transduce signals initiated by ligand binding to NogoR (Foumier et al., J Neurosci 22:8876-8883 (2002); Hunt et al., J Neurocytol 31:93-120 (2002)). Both p75 and LINGO-1 have been identified as co-receptors of NogoR and function in inhibiting neurite outgrowth (Wong et al., Nature 420:74-78 (2002); Mi et al., Nat Neurosci 7:221-228 (2004)).
Since the interaction of Nogo, OMgp and MAG to the NogoR/p75/LINGO-1 receptor complex inhibits neurite outgrowth, researchers have focused their efforts in disrupting ligand binding to the receptor complex. Antibodies against Nogo have been used to overcome the inhibitory effect of Nogo (Domeniconi et al., Neuron 35:283-290 (2002)). Similarly, the neurite outgrowth inhibition of MAG was overcome using antibodies against MAG (Tang et al., Mol Cell Neurosci 18:259-269 (2001)). Efforts have been undertaken to neutralize NogoR-mediated signaling pathway. Antagonistic peptides against NogoR, soluble forms of NogoR, and antibodies against NogoR have been shown to promote axonal outgrowth in vitro and have thus identified NogoR as a potential therapeutic target for spinal cord injuries (Domeniconi et al., Neuron 35:283-290 (2002); Grandpre et al., Nature 417:547-551 (2002)). Compositions which prevent NogoR activity, either by preventing ligand binding or by preventing downstream signaling, would clearly be useful in combating spinal cord dysfunction.
As of today, there a few options available to treat or ameliorate the loss of motor/sensory function or paralysis associated with spinal cord injuries, stroke or multiple sclerosis. There is a clear need for the identification and characterization of compositions, such as antibodies, including fully human antibodies that bind NogoR and allow axonal/neurite outgrowth, as well as methods of treating or ameliorating paralysis using such compositions. In particular, there is a need for such compositions, methods of treating or ameliorating spinal cord injuries or stroke for use in humans.